We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Direct Effects of Furosemide on Renin Secretion and Preglomerular Resistance.
- Authors
Castrop, H.; Hansen, P.; Huang, Y.; Mizel, D.; Oppermann, M.; Lorenz, J.; Briggs, J.; Schnermann, J.
- Abstract
Objective: Acute administration of loop diuretics like furosemide leads to a stimulation of renin secretion and a dilatation of the afferent arteriole. It is widely believed that both effects are the result of inhibition of NKCC2 in the apical membrane of macula densa (MD) cells and subsequent alterations in MD-dependent signaling pathways. Besides NKCC2, loop diuretics also inhibit NKCC1, the second isoform of the Na/K/2Cl cotransporter, with equal potency. Since NKCC1 is expressed in the afferent arteriole and extraglomerular mesangium of the kidney we determined the influence of furosemide on renin secretion and preglomerular resistance in NKCC1-deficient mice in order to discriminate between effects of NKCC2 in MD cells and potential direct effects via inhibition of NKCC1. Methods: Plasma renin concentration (PRC) was determined from tail blood samples of conscious mice by radio-immuno assay. The effect of furosemide on preglomerular resistance was determined in the isolated perfused afferent arteriole model. Results: Baseline PRC was 259 ± 61 in NKCC1+/+ (n = 9) compared to 1,232±261 ng Ang I/ml h in NKCC1-/-mice (n = 13; p < 0.01). The high basal PRC in NKCC1-/-mice was paralleled by an increased renin mRNA expression and by a recruitment of granular cells. Acute administration of furosemide (50 mg/kg i.p.) increased PRC 6.9 fold in wild type mice, to 1,794±229 ng Ang I/ml h (n = 9; p<0.001 compared to control). PRC in NKCC1+/+mice after administration of furosemide was comparable to basal PRC in NKCC1-/-mice (p = 0.14). In contrast, furosemide increased PRC only 1.6 fold in NKCC1-/-mice, to 1,925 ± 277 ng Ang I/ml h (n = 13; p = 0.08). In isolated perfused afferent arterioles dissected from wild type mice, furosemide led to a dose-dependent vasodilatation after preconstriction with Ang II (diameter 4.2 ± 0.5, 4.8 ± 0.6, 5.9± 0.5, 7.6 ± 0.6 and 8.2± 0.8µm, at 0µM, 30µM, 300µM, 1.5µM and 3µM of furosemide, respectively), but it had no significant effect on vessels from NKCC1-/-mice. Conclusions: These data suggest that besides modulating the macula densa pathway, furosemide also stimulates renin secretion and lowers preglomerular resistance by directly inhibiting NKCC1.
- Subjects
FUROSEMIDE; DIURETICS; ASPARTIC proteinases; RENIN; JUXTAGLOMERULAR apparatus; EXCRETION; SECRETION; BIOLOGICAL transport
- Publication
Kidney & Blood Pressure Research, 2004, Vol 27, Issue 5/6, p295
- ISSN
1420-4096
- Publication type
Article